BR122017005939B1 - PROCESS FOR MANUFACTURING SULFAMIDE PYRIMIDINE DERIVATIVES - Google Patents

Abstract

PROCESS FOR MANUFACTURING SULFAMIDE PYRIMIDINE DERIVATIVES The invention relates to a process for manufacturing the compound of formula I, wherein R is H, (C1-C6) alkyl or benzyl, or a salt thereof, the process comprising reaction of the compound of formula I-1 where X is Br, Cl or F, or a salt thereof, with the compound of formula I-2 where R is H, (C1-C6) alkyl or benzyl, or a salt thereof, in the presence of a base, and, when X is Br or Cl, in the presence of tetra-n-butyl ammonium fluoride hydrate or cesium fluoride. The invention further relates to the compound of formula I-1 and uses thereof.

Description

Em que R presenta H, alquila (C1-C6) ou benzila.[0001] The present invention relates to a process for the manufacture of pyrimidine sulfamide derivatives of formula I

Where R represents H, (C1-C6) alkyl or benzyl.

[0002] The compounds of formula I are endothelin receptor antagonists which were first disclosed in WO 02/053557. Among these compounds, macitentan (compound of formula I where R is n-propyl; chemical names: N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy ]4-pyrimidinyl]-N'-propylsulfamide or N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl}-N '-propylsulfuric diamide) is an endothelin receptor antagonist that is notably approved by the US Food and Drug Administration and European Commission for the treatment of pulmonary arterial hypertension. The last step of one of the potential preparation routes described in WO 02/053557, called "Possibility A" and "Possibility B", can be summarized as shown in Scheme A1 below.

Scheme A1

[0003] In Scheme Al, G1 represents a reactive residue, and preferably a chlorine atom.

[0004] The preparation of macitentan according to "Possibility B" of WO 02/053557 was further described in Bolli et al., J. Med. chem. (2012) 55, 7849-7861. Therefore:

[0005] . KOtBu was added to a solution of large excess ethylene glycol in dimethoxy ethane and the compound of formula I1 where G1 is Cl (see Scheme A1 above) was added thereto; after heating at 100°C for 70 h, work involving extraction and purification by column chromatography, the compound of formula I2 was obtained in 86% yield; and

[0006] . the compound of formula I2 was added to a suspension of NaH in THF, the mixture stirred and diluted with DMF before addition of 5-bromo-2-chloropyridimine; after heating to 60°C and work involving crystallization and extraction steps, macitentan was obtained in a yield of 88%.

[0007] The methods for manufacturing macitentan described above, however, are not suitable for manufacturing macitentan in sufficient purity unless numerous purification steps are performed to remove impurities, including ethylene glycol, from the compound of formula I2 before to perform the step corresponding to "Possibility B" of WO 02/053557. In this regard, it should be mentioned that ethylene glycol is actually harmful and quite difficult to remove by distillation due to a high boiling point.

[0008] Furthermore, the compound of formula I where R is H has been disclosed in WO 2009/024906. The last steps of potential preparation routes described in WO 2009/024906 can be summarized as shown in Scheme A2 below.

Scheme A2

[0009] In Scheme A2, G2 represents a reactive group such as a halogen atom (preferably a chlorine atom) and PG represents a protecting group such as a benzyl group or a 4-methoxy- or 2,4-dimethoxy group benzyl.

[0010] According to the route disclosed in WO 2009/024906 (see Scheme A2), the compound of formula I0 can be reacted with ethylene glycol in the presence of a base, in the presence or absence of an additional solvent and preferably at elevated temperatures . The resulting intermediate can then be reacted with 5-bromo-2-chloropyrimidine or an equivalent reactive entity in the presence of a strong base in a solvent such as THF, DMF, dioxane, etc., or mixtures thereof. The PG protecting group can then be removed by standard methods to provide the compound of formula I where R is H.

[0011] The manufacturing route disclosed in WO 2009/024906, which can also be tried with PG = Fmoc or PG = Boe, again has the disadvantage of using ethylene glycol in one of its later stages.

[0012] Although manufacturing routes using ethylene glycol in one of the final stages have known disadvantages, a person skilled in the art, however, does not know of any true alternative route that offers a reasonable expectation of success. In particular, the skilled person would expect that the reaction shown in Scheme 0 below, where X represents a halogen atom such as fluorine, bromine or chlorine and R represents hydrogen or alkyl is not likely to proceed because the pyrimidine ring system of the compound of the Formula I-1 is deactivated by electronic effects, thereby making a nucleophilic aromatic substitution unlikely.

scheme 0

[0013] In this regard, one can, for example, refer to the book March's Advanced Organic Chemistry (see the section “Reactivity” of the chapter “Aromatic, Nucleophilic and Organometallic Substitution” in March's Advanced Organic Chemistry, Reactions, Mechanisms and Structures , sixth edition (2007), 864-867). The person skilled in the art thus knew that the compound of formula I1 is deactivated towards a nucleophilic aromatic substitution due to its alkoxy side chain; moreover, the skilled technician knew at the same time that sulfamide or n-propylamino sulfonamide are bad nucleophiles (mesomeric effect leading to a delocalization of the N-alone pair to sulfur).

[0014] In accordance with the expected failure of the nucleophilic aromatic substitution reaction the inventors could thus observe that the reaction of the compound of formula I-1 where X is chlorine with standard fluorinating agents such as KF or NaF did not yield the fluorinated intermediate with sufficient yield and purity. Furthermore, it was also observed that the reaction of the compound of formula I-1 where X is chlorine with sulfamide did not take place at 70°C in DMSO. These findings confirm the fact that the compound of formula I-1 is not suitable for nucleophilic aromatic substitution, in particular if the nucleophile intended to be used in the nucleophilic aromatic substitution is a bad nucleophile like sulfamide.

[0015] It has now surprisingly been discovered that an alternative route to the compounds of formula I was nevertheless possible in which the sulfamide function would be introduced in the last step by nucleophilic substitution on the pyrimidine nucleus. The introduction of the sulfamide function via nucleophilic substitution on the pyrimidine nucleus was, however, only possible in a satisfactory manner when using the specific reaction conditions found by the inventors and described below.

[0016] Thus, an alternative route required obtaining a fluorinated intermediate with high purity, the result of which could be properly obtained using the fluorinating agent tetra-n-butyl ammonium fluoride hydrate or cesium fluoride.

[0017] A significant advantage of this alternative route is that it allows the use in the last step of a pyrimidine derivative already having a functionalized secondary chain at position 6 (i.e. the secondary chain of 2-(5-bromo-pyrimidin-2- yloxy)-ethoxy), which avoids the use of an excess of ethylene glycol (needed at some point to obtain the 2-(5-bromo-pyrimidin-2-yloxy)-ethoxy side chain - see e.g. WO 02 /053557 or Bolli et al., J. Med. Chem. (2012), 55, 7849 - 7861) at a later stage of the manufacturing process. Furthermore, this route allows the use of a single intermediate to prepare a single step in any compound of formula I where R represents H, (C1-C6) alkyl or benzyl.

[0018] Various embodiments of the invention are presented below:

Em que R é H, alquila (C1-C6) ou benzila, ou um sal do mesmo, o processo compreendendo a reação do composto da fórmula I-1

Em que X é bromo, cloro ou flúor (e em particular cloro ou flúor), com o composto da fórmula I-2

Em que R é H, alquila (C1-C6) ou benzila, ou um sal do composto da fórmula I-2, a reação sendo executada na presença de uma base em um solvente orgânico aprótico polar ou uma mistura polar de solventes orgânicos apróticos, e quando X é bromo ou cloro, na presença de hidrato de fluoreto de amônio tetra-n-butila ou fluoreto de césio.[0019] 1) The invention primarily relates to a process for manufacturing the compound of formula I

Where R is H, (C1-C6) alkyl or benzyl, or a salt thereof, the process comprising reacting the compound of formula I-1

Where X is bromine, chlorine or fluorine (and in particular chlorine or fluorine), with the compound of formula I-2

Where R is H, (C1-C6) alkyl or benzyl, or a salt of the compound of formula I-2, the reaction being carried out in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents, and when X is bromine or chlorine, in the presence of tetra-n-butyl ammonium fluoride hydrate or cesium fluoride.

[0020] 2) Preferably, the base used in the process according to embodiment 1) will be selected from the group consisting of NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethyl amine, tert potassium -butylate, Na2CO3, K2CO3 and Cs2CO3 (and notably from the group consisting of NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, potassium tert-butylate, Na2CO3 and K2CO3 ).

[0021] 3) In particular, the base used in the process according to embodiment 1) will be K2CO3.

[0022] 4) Preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the process according to one of embodiments 1) to 3) will be carried out at a temperature of 20 to 140°C.

[0023] 5) More preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the process according to one of embodiments 1) to 3) will be carried out at a temperature of 60 to 80°C.

[0024] 6) Also preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the process according to one of embodiments 1) to 5) will be such that 0.9 to 4 equivalents (and in particular 0.9 to 1.5 equivalents) of the compound of formula I-2 are used per equivalent of the compound of formula I-1.

[0025] 7) More preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the process according to one of embodiments 1) to 5) will be such that 1 to 3 equivalents (e.g. 1 to 1.5 equivalents and notably 1 to 1.2 equivalents) of the compound of formula I-2 are used per equivalent of the compound of formula I-1.

[0026] 8) Furthermore, the reaction of the compound of formula I-1 wherein X is chlorine with the compound of formula I-2 in the process according to one of embodiments 1) to 7) will preferably be such that 1.1 to 10 equivalents of tetra-n-butyl ammonium fluoride hydrate are used per equivalent of compound of formula I-1.

[0027] 9) In particular, the reaction of the compound of formula I-1 wherein X is chlorine with the compound of formula I-2 in the process according to one of embodiments 1) to 7) will be such that 2 to 4 equivalents of tetra-n-butyl ammonium fluoride hydrate are used per equivalent of the compound of formula I-1.

[0028] 10) Preferably also, the reaction of the compound of formula I-1 with the compound of formula I-2 in the process according to one of embodiments 1) to 9) will be such that 1.5 to 10 equivalents (and notably 1.5 to 5 equivalents) of base are used per equivalent of the compound of formula I-1.

[0029] 11) More preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the process according to one of embodiments 1) to 9) will be such that 2 to 7 equivalents (and notably 2 to 4 equivalents) of K2CO3 are used per equivalent of the compound of formula I-1.

[0030] 12) According to a preferred embodiment of this invention, the reaction of the compound of formula I-1 with the compound of formula I-2 in the process according to one of embodiments 1) to 11) will be such that the organic solvent polar aprotic or polar mixture of aprotic organic solvents is selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, sulfolane and a mixture of two solvents, whereby the first of these two solvent is selected from the group consisting of toluene and DCM, and the second of these two solvents is selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, sulfolane, and a mixture of toluene, DCM and a third solvent selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane.

[0031] 13) Preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the process according to embodiment 12) will be such that the polar aprotic organic solvent or polar mixture of aprotic organic solvents comprises sulfoxide of dimethyl.

[0032] 14) More preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the process according to embodiment 12) will be carried out using dimethyl sulfoxide as a solvent.

[0033] 15) Preferably, when the compound of formula I-1 is such that X is bromine or chlorine, the process of embodiments 1) to 14) will be carried out in the presence of tetra-n-butyl ammonium fluoride hydrate.

[0034] 16) In a further preferred embodiment, the process of embodiments 1) to 15) will be such that X is chlorine and the reaction of the compound of formula I-1 with the compound of formula I-2 is carried out in the presence of hydrate of tetra-n-butyl ammonium fluoride and using dimethyl sulfoxide as solvent.

[0035] 17) Alternatively, when the compound of formula I-1 is such that X is bromine or chlorine, the process of embodiments 1) to 14) will preferably be carried out in the presence of cesium fluoride.

[0036] 18) Preferably, the process of embodiment 16) will be such that 1.1 to 4 equivalents (and notably 1.1 to 1.5 equivalents or 1.1 to 1.3 equivalents) of cesium fluoride are used per equivalent of the compound of formula I-1.

[0037] 19) In particular, the process of embodiment 16) will be such that 2.5 to 3.5 equivalents of cesium fluoride are used per equivalent of the compound of formula I-1.

[0038] 20) According to a variant of the process of embodiments 1) to 19), the compound of formula I or its salt will be such that R is H.

[0039] 21) According to another process variant of embodiments 1) to 19), the compound of formula I or its salt is such that R is (C1-C6) alkyl.

[0040] 22) Preferably, in the process according to embodiment 21), the compound of formula I or its salt will be such that R is n-propyl.

[0041] 23) According to yet another variant of the process of embodiments 1) to 19), the compound of formula I or its salt will be such that R is benzyl.

[0042] 24) The invention also relates to new synthetic intermediates useful in the preparation of pyrimidine sulphamide derivatives of formula I, namely the compounds of formula I-1

[0043] Wherein X is bromine, chlorine or fluorine, and the salts of the compounds.

[0044] 25) According to a variant of embodiment 24), the compound of formula I-1 or its salt will be such that X is chlorine.

[0045] 26) According to the other variant of embodiment 24), the compound of formula I-1 or its salt will be such that X is fluorine.

[0046] 27) The invention further relates to the use of a compound of formula I-1 according to one of embodiments 24) to 26), or a salt thereof, in a process for manufacturing the compound of formula I as defined in embodiment 1) or a salt thereof.

[0047] 28) According to a variant of embodiment 27), the compound of formula I-1 or its salt in the use of embodiment 27) will be such that X is chlorine.

[0048] 29) According to the other variant of embodiment 27), the compound of formula I-1 or its salt in the use of embodiment 27) will be such that X is fluorine.

[0049] 30) According to an important variant of the use of embodiments 27) to 29), the compound of formula I or its salt will be such that R is H.

[0050] 31) According to another important variant of the use of embodiments 27) to 29), the compound of formula I or its salt will be such that R is (C1-C6) alkyl.

[0051] 32) Preferably, in the use according to embodiment 31), the compound of formula I or its salt will be such that R is n-propyl.

[0052] 33) According to yet another important variant of the use of embodiments 27) to 29), the compound of formula I or its salt will be such that R is benzyl.

[0053] 34) The invention further relates to the use of a compound of formula I-1 according to embodiment 25), or a salt thereof, in a process for manufacturing the compound of formula I-1 as defined in embodiment 26) or a salt thereof.

[0054] 35) Preferably, the use according to embodiment 34) will be such that the process for manufacturing the compound of formula I-1 as defined in embodiment 26) will comprise reacting the compound of formula I-1 according to modality 25), or a salt thereof, with tetra-n-butyl ammonium fluoride hydrate.

[0055] 36) According to a variant of use according to embodiment 35), the reaction of the compound of formula I-1 according to embodiment 25), or a salt thereof with tetra ammonium fluoride hydrate -n-butyl will be performed in the presence of a base.

[0056] 37) Preferably, the use according to embodiment 36) will be such that the base is selected from the group consisting of NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethyl amine , potassium tert-butylate, Na2CO3, K2CO3 and Cs2CO3 (and in particular such that the base is selected from the group consisting of NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethyl amine , potassium tert-butylate, Na2CO3 and K2CO3).

[0057] 38) More preferably, the use according to embodiment 36) will be such that the base is K2CO3.

[0058] 39) According to another variant of use according to embodiment 35), the reaction of the compound of formula I-1 according to embodiment 25), or a salt thereof, with ammonium fluoride hydrate tetra-n-butyl will be performed in the absence of a base.

[0059] 40) The invention further relates to a use as defined in one of embodiments 34) to 39), whereby the compound of formula I-1 thus obtained is then used to manufacture a compound of formula I as defined in mode 1).

[0060] 41) Preferably, the use of embodiment 40) will be such that the manufacture of a compound of formula I as defined in embodiment 1) will be carried out by reacting the compound of formula I-1 thereby obtained, or a salt thereof , with a compound of formula I-2 as defined in embodiment 2), or a salt thereof in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents.

[0061] 42) Preferably, the base used in the process according to embodiment 41) will be selected from the group consisting of NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethyl amine, tert -potassium butylate, Cs2CO3, Na2CO3 and K2CO3.

[0062] 43) In particular, the base used in the process according to embodiment 41) will be K2CO3.

[0063] 44) According to a preferred embodiment of using embodiments 41) to 43), the reaction of the compound of formula I-1 with the compound of formula I-2 will be such that the polar aprotic organic solvent or solvent mixture of aprotic organic solvents is selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, sulfolane and a mixture of two solvents, whereby the first of these solvents is selected from the group consists of toluene and DCM and the second of these two solvents is selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, sulfolane, and a mixture of toluene, DCM and a third solvent selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane.

[0064] 45) Preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the use according to embodiment 44) will be such that the polar aprotic organic solvent or polar mixture of aprotic organic solvents comprises sulfoxide of dimethyl.

[0065] 46) More preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the use according to embodiment 44) will be carried out using dimethyl sulfoxide as a solvent.

[0066] 47) As an alternative preferred embodiment, the use according to embodiment 34) will be such that the process for making the compound of formula I-1 as defined in embodiment 26) will comprise reacting the compound of formula I-1 according to embodiment 25), or a salt thereof, with cesium fluoride in the presence of a base.

[0067] 48) Preferably, the use according to embodiment 47) will be such that the base is selected from the group consisting of NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethyl amine , potassium tert-butylate, Na2CO3, K2CO3 and Cs2CO3.

[0068] 49) More preferably, the use according to embodiment 47) will be such that the base is K2CO3.

[0069] 50) According to a preferred embodiment of using embodiments 47) to 49), the reaction of the compound of formula I-1 with the compound of formula I-2 will be such that the polar aprotic organic solvent or polar mixture of aprotic organic solvents is selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, sulfolane and a mixture of two solvents, whereby the first of these two solvents is selected from the group consists of toluene and DCM and the second of these two solvents is selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, sulfolane, and a mixture of toluene, DCM and a third solvent selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane.

[0070] 51) Preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the use according to embodiment 50) will be such that the polar aprotic organic solvent or polar mixture of aprotic organic solvents comprises sulfoxide of dimethyl.

[0071] 52) More preferably, the reaction of the compound of formula I-1 with the compound of formula I-2 in the use according to embodiment 50) will be carried out using dimethyl sulfoxide as a solvent.

Em que R é H, alquila (C1-C6) ou benzila ou para fabricar um sal do mesmo, o processo compreendendo a reação do composto da fórmula I1, o processo compreendendo as seguintes etapas: a) A reação do composto da fórmula I-1cl

Ou um sal do mesmo, com hidrato de fluoreto de amônio tetra n-butila ou fluoreto de césio na presença de uma base em um solvente orgânico aprótico polar ou uma mistura polar de solventes orgânicos apróticos, para fornecer o composto da fórmula I-1F

b) A reação do composto da fórmula I-1F obtido na etapa a) com um composto da fórmula I-2

Onde R é H, alquila (C1-C6) ou benzila, ou um sal do mesmo, na presença de uma base em um solvente orgânico aprótico polar ou uma mistura polar de solventes orgânicos apróticos para fornecer o composto da fórmula I ou um sal do mesmo.[0072] 53) The present invention also relates to a process for manufacturing the compound of formula I

Where R is H, (C1-C6) alkyl or benzyl or to make a salt thereof, the process comprising reacting the compound of formula I1, the process comprising the following steps: a) Reacting the compound of formula I- 1cl

Or a salt thereof, with tetra n-butyl ammonium fluoride hydrate or cesium fluoride in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents, to give the compound of formula I-1F

b) The reaction of the compound of formula I-1F obtained in step a) with a compound of formula I-2

Where R is H, (C1-C6) alkyl or benzyl, or a salt thereof, in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents to provide the compound of formula I or a salt of the same.

[0073] 54) Preferably, step a) of the manufacturing process of embodiment 53) will be carried out by reacting the compound of formula I-1Cl with cesium fluoride.

[0074] 55) Preferably, the base used in step a) of the manufacturing process of embodiment 53) or 54) will be selected from the group consisting of NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec- 7-ene, triethyl amine, potassium tert-butylate, Na2CO3, K2CO3 and Cs2CO3.

[0075] 56) More preferably, the base used in step a) of the manufacturing process of embodiment 53) or 54) will be K2CO3.

[0076] 57) Preferably, the base used in step b) of the manufacturing process of one of the embodiments 53 to 56) will be selected from the group consisting of NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7 -ene, triethyl amine, potassium tert-butylate, Na2CO3, K2CO3 and Cs2CO3.

[0077] 58) More preferably, the base used in step b) of the manufacturing process of one of embodiments 53) to 56) will be K2CO3.

[0078] 59) In particular, K2CO3 will be used as the basis in both steps a) and b) of the manufacturing process 53) or 54).

[0079] 60) According to a preferred embodiment of the process according to one of embodiments 53) to 59), each of the polar aprotic organic solvent or polar mixture of aprotic organic solvents used in step a) and step b) will be independently selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, sulfolane and a mixture of two solvents, whereby the first of these two solvents is selected from the group consisting of toluene and DCN and the second of these two solvents is selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, sulfolane, and a mixture of toluene, DCM and a third solvent selected from the group that consists of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane.

[0080] 61) Preferably, the process according to embodiment 60) will be such that each of the polar aprotic organic solvents or polar mixtures of aprotic organic solvents used in step a) and step b) will comprise dimethyl sulfoxide.

[0081] 62) More preferably, step a) and step b) of the process according to embodiment 60) will be individually carried out using dimethyl sulfoxide as a solvent.

[0082] 63) In particular, the process according to embodiment 53) will be such that: Step a) of the manufacturing process will be carried out by reacting the compound of formula I-1Cl with cesium fluoride, and dimethyl sulfoxide will be used as solvent in both step a) and b).

[0083] 64) Preferably, in each of steps a) and b) of the manufacturing process of embodiment 63) the base will be independently selected from the group consisting of NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7 -ene, triethyl amine, potassium tert-butylate, Na2CO3, K2CO3 and Cs2CO3.

[0084] 65) More preferably, the base will be Cs2CO3 in step a) of the manufacturing process of embodiment 63) or 64).

[0085] 66) According to a preferred variant of the invention, the manufacturing process according to one of the embodiments 53) to 65) will be such that R is H.

[0086] The present invention thus notably relates to manufacturing processes, compounds and uses as defined in one of embodiments 1), 24), 27), 34) and 53) or to these manufacturing processes, compounds and further limited uses in consideration of their respective dependencies by the characteristics of any of the modalities 2) to 35), 25) and 26), 28) to 33), 35) to 39) and 54) to 67). In particular, based on the dependencies of the different modalities as disclosed above, the following modalities of manufacturing process, compound and use are hereby possible and intended and specifically disclosed in individualized form: 1, 2+1, 3+1, 4+1, 4+2+1, 4+3+1, 5+1, 5+2+1, 5+3+1, 6+1, 6+3+1, 6+5+1, 6+ 5+2+1, 6+5+3+1, 7+1, 7+3+1, 7+5+1, 7+5+2+1, 7+5+3+1, 8+1, 8+3+1, 8+5+1, 8+5+2+1, 8+5+3+1, 8+7+1, 8+7+3+1, 8+7+5+1, 8+7+5+2+1, 8+7+5+3+1, 9+1, 9+3+1, 9+5+1, 9+5+2+1, 9+5+3+ 1, 9+7+1, 9+7+3+1, 9+7+5+1, 9+7+5+2+1, 9+7+5+3+1, 10+1, 10+ 3+1, 10+5+1, 10+5+2+1, 10+5+3+1, 10+7+1, 10+7+3+1, 10+7+5+1, 10+ 7+5+2+1, 10+7+5+3+1, 10+9+1, 10+9+3+1, 10+9+5+1, 10+9+5+2+1, 10+9+5+3+1, 10+9+7+1, 10+9+7+3+1, 10+9+7+5+1, 10+9+7+5+2+1, 10+9+7+5+3+1, 11+1, 11+3+1, 11+5+1, 11+5+2+1, 11+5+3+1, 11+7+1, 11+7+3+1, 11+7+5+1, 11+7+5+2+1, 11+7+5+3+1, 11+9+1, 11+9+3+1, 11+9+5+1, 11+9+5+2+1, 11+9+5+3+1, 11+9+7+1, 11+9+7+3+1, 11+9+ 7+5+1, 11+9+7+5+2+1, 11+9+7+5+3+1, 12+1, 12+3+1, 12+5+1, 12+5+ 2+1 , 12+5+3+1, 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67+62+60+58+56+54+53, 67+62+60+59+53, 67+62+60+59+54+ 53, 67+63+53, 67+65+63+53 and 67+65+64+63+53.

[0087] In the list above, the numbers refer to the modalities according to their numbering provided above, while “+” indicates dependence from another modality. The different individualized modalities are separated by commas. In other words, “5+2+1”, for example, refers to modality 5) depending on modality 2), depending on modality 1), that is, modality “5+2+1” corresponds to modality 1) additionally limited by the characteristics of modalities 2) and 5). Similarly, “9+7+3+1” refers to modality 9) depending mutatis mutandis on modality 7) and 3) depending on modality 1), i.e. modality “9+7+3+'” corresponds to modality modality 1) additionally limited by the characteristics of modality 3), additionally limited by the characteristics of modality 7) and 9).

[0088] The methods for preparing the starting compound, that is, the compounds of formulas I-1 and I-2 as defined in embodiment 1), are described in the section "Preparation of starting materials" below, while the methods to obtain the compound of formula I from the compound of formula I-1 and the compound of formula I-2 as defined in embodiment 1) are described in the section "Uses of compound of formula I-1" below.

PREPARATION OF STARTING MATERIALS

[0089] The compound of formula I-1 can be prepared as summarized in Scheme 1 below.

scheme I

[0090] 5-bromo-2-chloropyrimidine (compound IA) can be reacted (Scheme 1) with ethylene glycol in the presence of a base (e.g. tBuOK or DBU) providing 2-((5-bromopyrimidin-2-yl)oxy ) ethanol (compound IB). Another method to obtain compound IB would be to perform the reaction of 5-bromo-2-chloropyrimidine with 2-(tert-butoxy)ethanol in the presence of a base such as tBuOK and then removal of the tert-butyl protecting group using aq HCl . conc. Or using formic acid followed by aq. NaOH; yet a further method to obtain compound IB would be to proceed as described in Kokatla and Laksham, Org. Lett. (2010), 12, 4478-4481 . Compound IB can then be reacted, in a polar aprotic solvent in the presence of a base, with 5-(4-bromophenyl)-4,6-dichloropyrimidine or 5-(4-bromophenyl) )-4,6-dibromopyrimidine (compound of formula Ic where X is Br or Cl) thereby providing the compound of formula I-1 where X is Br or Cl. To obtain the compound of formula I-1 where X is F, the compound of formula I-1 where X is Br or Cl can be reacted with TBAF hydrate in the presence or absence of a base in a polar aprotic solvent. The compound of formula Ic where X is Br or Cl can be prepared by methods similar to those described in Bolli et al., J. Med. chem. (2012), 55, 7849-7861 or those described in WO 2010/091824.

[0091] The compound of formula I-2 is commercial (when R is H) or can be prepared by methods similar to those described in Bolli et al., J. Med. chem. (2012), 55, 7849-7861 to obtain the compound of formula I-2 wherein R is n-propyl (when R is (C1-C6) alkyl or benzyl). USES OF THE COMPOUND OF FORMULA I-1

[0092] The compound of the formula I-1 where X is Br or Cr can notably be used to directly obtain the compounds of the formula 1 (see for example embodiment 1 above) or to obtain the compound of the formula I-1 where X is F (by reaction with TBAF in the presence or absence of a base). The compound of formula I-1 where X is F can notably be used to obtain compounds of formula I (see, for example, embodiment 1 above).

ABBREVIATIONS AND TERMS USED IN THIS TEXT Abbreviations:

[0093] The following abbreviations are used throughout the specification and examples:

[0094] Ac - acetyl

[0095] Approx. - approx.

[0096] Here - watery

[0097] BOP 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate

[0098] DAD - diode set detection

[0099] DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene

[0100] DCM - dichloromethane

[0101] DMAC - dimethyl acetamide

[0102] DME - 1,2-dimethoxy ethane

[0103] DMF - dimethyl formamide

[0104] DMSO - dimethyl sulfoxide

[0105] EA - ethyl acetate

[0106] Eq. Equivalent(s)

[0107] Fmoc - 9-fluorenyl methoxy carbonyl

[0108] GC - gas chromatography

[0109] Hept - heptane

[0110] iPrOH - isopropanol

[0111] iPrOAc - isopropyl acetate

[0112] IT - internal temperature

[0113] LC-MS - liquid chromatography - mass spectroscopy

[0114] MeCN - acetonitrile

[0115] MS - mass spectroscopy

[0116] NMP - N-methyl-2-pyrrolidone

[0117] Org. - organic

[0118] RT - room temperature

[0119] % y/y - percentage determined by area ratio

[0120] TBAF - tetra-n-butyl ammonium fluoride

[0121] TFA - trifluoroacetic acid

[0122] THF - tetrahydrofuran

[0123] TR - retention time Definitions of specific terms used in this text:

[0124] The following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention as well as other specific terms in that text and are intended to apply uniformly throughout the specification and claims, unless a definition otherwise expressly provided provides a broader or narrower definition:

[0125] . the term "alkyl" refers to a straight or branched chain alkyl group containing one to six carbon atoms. The term "(C1-Cx) alkyl" (x being an integer) refers to a straight or branched chain alkyl group containing 1 to x carbon atoms. For example, an alkyl group (C1-C6) contains one to six carbon atoms. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.

[0126] . the term "halogen" refers to fluorine, chlorine, bromine or iodine, and preferably to fluorine or chlorine.

[0127] . the term “polar aprotic solvent” refers to a solvent that does not have an acidic hydrogen and has an electric dipole moment of at least 1.5 Debye. Representative examples of polar aprotic solvents include MeCN, chlorobenzene, EA, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO or sulfolane.

[0128] . The expression “polar mixture of aprotic solvents” refers to a mixture of solvents that does not have an acidic hydrogen, whereby the mixture has an electric dipole moment of at least 1.5 Debye. Representative examples of aprotic solvent mixtures include, but are not limited to: a mixture of two solvents, whereby the first of these solvents is selected from the group consisting of toluene and DCM and the second of these solvents is selected from the group consisting of MeCN , chlorobenzene, EA, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane; or a mixture of toluene, DCM and a solvent selected from the group consisting of MeCN, chlorobenzene, EA, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane.

[0129] . The expression "room temperature" as used herein refers to a temperature of 20 to 30°C, and preferably 25°C.

[0130] . Unless used in relation to temperatures, the term "about" or "approximately" placed before a numerical value "X" refers in the current order to a range extending from X minus 10% of X to X plus 10% of X, and preferably to a range extending from X minus 5% of X to X plus 5% of X. In the specific case of temperatures, the term "approximately" placed before a temperature "Y" refers in the current application to a range extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to a range extending from Y minus 5°C to Y plus 5°C.

[0131] Specific embodiments of the invention are described in the Examples below, which serve to illustrate the invention in more detail without limiting its scope in any way.

EXAMPLES

[0132] All temperatures given are outside temperatures and are stated in °C. Compounds were characterized by 1H-NMR (400 MHz) or 13C-NMR (100 MHz) (Bruker; chemical shifts δ are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet; p = pentet, hex = hexet, hept = heptet, m = multiplet, br = wide, coupling constants are given in Hz); by GC-MS; by LC-MS (Finnigan Navigator with Binary Pump HP 1100 and DAD). LC-MS method 1 parameters: Injection volume: 2 μL Column: Kinetex C18, 2.6 μm, 2.1 x 50 mm Column flow rate: 1 mL/min Eluents: Eluent A: water + 0.08% TFA Eluent B: MeCN + 0.012% TFA Gradient 2.0 min 2.8 min 3.0 min 95% 95% 5% BBB Temperature: : 40°C Detector wavelength 210 nm Method parameters LC-MS 2: Injection volume: 0.40 μL Column: Hypersil Gold, 1.7 μm, 3.0 x 50 mm Flow rate 1.2 mL/min column: Eluents: Eluent A: water + 0.04% TFA Eluent B: MeCN Gradient: 0.0 min 2% B 4.5 min 90% B 5.7 min 90% B 6.0 min 2% B Temperature: 40°C Detector wavelength 210 nm LC-MS method parameter 3:

Example 1: 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy-6-chloropyrimidine: Variant I:

[0133] 5-(4-bromophenyl)-4,6-dichloropyrimidine (26.7 g; 88.0 mmol) and 2-((5-bromopyrimidin-2-yl)oxy)ethanol (20 g; 91.3 mmol; 1.04 eq.; prepared as described in Kokatla and Lakshman, Org. Lett. (2010), 12, 4478-4481) were suspended in toluene (266 mL). KOtBu (11.3 g, 101 mmol, 1.15 eq.) was added portionwise at 10-20°C. The resulting mixture (white suspension to orange mixture) was stirred at 20-25°C. After 1.5 h, 40% citric acid aq. (100 mL) was added until the pH was around 2-3. The layers have been separated. The org. it was washed 3 times with water (100 ml) and concentrated to dryness to give crude title compound as an orange oil (46 g). MeOH (65 mL) was added and a yellow precipitate formed. More MeOH (160 mL) was added and the resulting suspension was slurried under reflux for 30 min. It was cooled to 20-25°C. It was filtered, rinsed with MeOH and dried in vacuo to give the title compound as a white powder (36.3g; 85% yield).

[0134] 1H-NMR (CDCl3) δ: 8.54 (s, 1H); 8.50 (s, 2H); 7.55-7.51 (m, 2H); 7.22-7.18 (m, 2H); 4.78-4.74 (m, 2H); 4.66-4.64 (m, 2H).

[0135] [M+1]+ = 485 and 487.

[0136] LC-MS (method 1): tR = 1.97 min; 96.5% y/y,

Variant II:

[0137] 5-(4-bromophenyl)-4,6-dichloropyrimidine (100 g; 329 mmol) and 2-((5-bromopyrimidin-2-yl)oxy)ethanol (72.1 g; 329 mmol; 1 eq .; prepared as described in Kokatla and Lakshman, Org. Lett. (2010), 12, 4478-4481) were suspended in toluene (1 L). 1,8-diazabicyclo[5.4.0]undec-7-ene (73.6 mL; 493 mmol; 1.5 eq.) was added dropwise at 20-40°C. The resulting mixture was stirred at 80-85 °C for 5 h. It was allowed to cool to 20-25°C. Water (1 L) was added. The layers have been separated. The org. was washed with an aq. to 10% citric acid (1 L). The layers were separated and the aq. was back-extracted with toluene (500 mL). The extracts from org. combined were washed with water. The toluene was exchanged with iPrOH in vacuo at 50-55°C. The resulting mixture was stirred at 50-55 °C for 2 h. It was cooled to 20-25 °C for 2 h, filtered and rinsed with iPrOH to give the title compound as a white powder (136 g; 85% yield). The product had NMR data equivalent to those obtained for the Variant I product.

Example 2: 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine: Variant I:

[0138] The compound of example 1 (20.0 g; 41.1 mmol; 1.0 eq.) and cesium fluoride (7.5 g; 49.3 mmol; 1.2 eq.) were suspended in DMSO (200 mL) . It was heated at 7075°C for 4 h. The brown reaction mixture was cooled to 20-25°C. It was diluted with EA (140 mL), washed with water (140 mL), aq. 10% HCl (140 mL) and brine (140 mL). It was concentrated to dryness to give the title compound as a crude yellow solid. This material was suspended in iPrOH (40 mL) and heated to reflux for 10 min. THF (5 mL) was added and the resulting mixture was heated to reflux for 10 min., whereby a clear solution was obtained. It was left alone at 20-25°C while being seeded at IT = 43°C. It was filtered, rinsed with iPrOH (5 mL) and dried in vacuo to give the title product as a yellow solid (17.9 g, 93% yield).

[0139] 1H-NMR (CDCl3) δ: 8.52 (s, 2H); 8.47 (d, J = 1.9 Hz, 1H); 7.55-7.51 (m, 2H); 7.36-7.33 (m, 2H); 4.84-4.82 (m, 2H), 4.72-4.70 (m, 2H).

[0140] [M+1]+ = 471 and 473.

[0141] LC-MS (method 1): tR = 1.92 min; 100% y/y,

Variant II:

[0142] The compound of example 1 (5.0 g; 10.3 mmol; 1.0 eq.) and TBAF.3H2O (5.4 g; 17.0 mmol; 1.7 eq.) were suspended in DMSO (50 mL). The mixture was stirred at 20-25°C for 6 h. EA was added (50 mL), followed by aq. sat. of CaCl2 (10 mL). The layers were separated and the org. it was washed 3 times with brine (50 mL each time), then once with water (25 mL). The org. was concentrated under reduced pressure to dryness. The residue was recrystallized from iPrOH (10 mL) and THF (1.25 mL) to give the title compound as a white powder (3.2 g, 66% yield).

[0143] The product had NMR data equivalent to those obtained for the product of variant I.

[0144] LCM-MS (method 1); tR = 1.92 min; 88% y/y.

Variant III:

[0145] A reactor was charged with the compound of example 1 (600 g; 1.23 mol; 1.0 eq.), cesium fluoride (562 g; 3.69 mol; 3.0 eq.), DMSO (3 L) and toluene (1.2 L). Toluene was distilled off and the remaining mixture was stirred at 70 °C for 2 h. After cooling to RT, EA (2.4 L) and water (2.4 L) were added. The layers have been separated, and the org. it was successively washed with 7.5% wt/v CaCl 2 solution (2.4 L), brine (2.4 L) and water (3 L). The solvent was exchanged with iPrOHO (2.4 L), THF (150 mL) was added, and the slurry was heated to reflux. The resulting solution was slowly cooled to room temperature. Filtration, washing with iPrOH (0.6 L) and drying provided the title compound as an off-white solid (526 g, 91% yield).

[0146] LC-MS (method 3): tR = 5.27 min; 99.3% purity.

Example 3: Preparation of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide: Variant I:

[0147] The compound of example 1 (25 g; 51.4 mmol), sulfamide (5.4 g; 56.5 mmol; 1.1 eq.), TBAF.3H20 (48.6 g, 154 mmol, 3 eq.) and sodium carbonate potassium (21.3 g, 154 mmol, 3 eq.) were suspended in DMSO (250 mL) at 2025 °C. The mixture was heated at 70-75 °C for 1 h. At that point, LC-MS indicated complete conversion. The reaction mixture was cooled to 10-15°C. Water (200 mL) and DCM (350 mL) were added (caution: exotherm). The layers were separated and the org. it was washed twice with water (200 ml). It was washed with aq. to 20% (200 mL) and water (200 mL; pH around 3-4). The org. was concentrated to dryness to give the crude title compound as an orange oil. This material was adsorbed onto Isolute (30 g) with DCM. This residue was purified on silica gel (300g) using EA as solvent (600ml) to give a white foam (26g). The latter was dissolved in EA (50 mL) and heated to reflux. Spontaneous crystallization was observed. It was heated to reflux for 10 min. More EA (50 mL) was added. Allowed to cool to 20-25°C, filtered, rinsed with EA and dried in vacuo to give the title compound as a white powder (12.6g; 45% yield).

[0148] The product had NMR data equivalent to those reported in the supporting information associated with Bolli et al., J. Med. chem. (2012), 55, 7849-7861.

Variant II:

[0149] The compound of example 1 (10 g; 20.6 mmol), sulfamide (2.2 g; 56.5 mmol; 1.1 eq.), TBAF.3H2O (16.2 g, 51.4 mmol, 2.5 eq. ) and potassium carbonate (7.1 g; 51.4 mmol; 2.5 eq.) were suspended in DMSO (50 mL) at 20-25°C. The mixture was heated to 70-75 °C for 1 h. At that point, LC-MS indicated complete conversion. The reaction mixture was cooled to 10-15°C. Water (100 mL) and DCM (100 mL) were added (caution: exotherm). The layers were separated and the org. was washed with brine (until pH = 11; 100 mL), aq. to 40% (until pH = 3; 100 mL), twice with brine (100 mL) and finally with water (50 mL). The mixture was concentrated to a residual volume of approx. 50 mL. It was sown at 20-25°C. Crystallization occurred slowly at 20-25°C. It was cooled to 4°C and stirred for 1 h. It was filtered, washed with cold DCM (10ml) and dried in vacuo to give the title compound as a white solid (7.1g, 63% yield).

[0150] The product had NMR data equivalent to those reported in the supporting information associated with Bolli et al., J. Med. chem. (2012), 55, 7849-7861.

Variant III:

[0151] The compound of example 1 (100 g; 206 mmol), sulfamide (21.7 g; 226 mmol; 1.1 eq.), TBAF.3H2O (162 g; 514 mmol; 2.5 eq.) and potassium carbonate ( 71 g; 514 mmol; 2.5 eq.) were suspended in DMSO (500 mL) at 2025 °C. The mixture was heated at 70-75 °C for 2 h. At that point, LC-MS indicated complete conversion. The reaction mixture was cooled to 10-15°C. Water (1 L) and EA (1 L) were added (caution: exotherm). The layers were separated and the org. was washed with brine (1 L). It was washed with a sat. CaCl2 solution. (1 L) followed by aq. to 40% (1 L), 3 times with brine (1 L) and finally with water (0.5 L). The mixture was seeded at RT and allowed to cool to 0 °C for 15 h. It was filtered, washed with cold EA (100ml) and dried in vacuo to give the title compound as a white solid (52g; 46% yield.

[0152] The product had NMR data equivalent to those reported in the supporting information associated with Bolli et al., J. Med. chem. (2012), 55, 7849-7861.

[0153] LC-MS (Method 2); tR = 2.80 min; 98.5% y/y.

Variant IV:

[0154] The compound of example 2 (2 g; 4.25 mmol), sulfamide (0.45 g; 4.68 mmol; 1.1 eq.) and potassium carbonate (1.5 g; 10.6 mmol; 2.5 eq.) were suspended in DMSO (10 mL). It was heated at 70°C for 15 h. The mixture was cooled to 20-25°C. A solution here. to 40% citric acid was added dropwise (20 mL), followed by DCM (20 mL). The layers were separated and the org. it was washed with brine (20 mL) and water (10 mL). The org layers. combined were concentrated under reduced pressure to a residual volume of approx. 20 mL. It was cooled to 0-5°C, washed with cold DCM (5 mL), filtered and dried under reduced pressure (40°C, 10 mbar) to give the title compound as a white solid (1.51 g, 65% Yield).

[0155] The product had NMR data equivalent to those reported in the supporting information associated with Bolli et al., J. Med. chem. (2012), 55, 7849-7861.

[0156] LC-MS (method 1); tR = 1.59 min; 99.0% y/y.

Variant V:

[0157] The compound of example 2 (2 g; 4.25 mmol), sulfamide (0.58 g; 6.00 mmol; 1.4 eq.), cesium fluoride (1.6 g; 10.4 mmol; 1.5 eq.) and sodium carbonate potassium (1.8 g; 12.7 mmol; 3 eq.) were suspended in DMSO (10 mL) at 20-25°C. The mixture was heated at 70-75 °C for 15 h. At that point, LC-MS (method 1) indicated complete conversion. The reaction mixture was cooled to 10-15°C, DCM (20 mL) and aq. 30% solution (20 mL) was added. The layers were separated and the org. was washed twice with aq. citric acid. to 30% before being concentrated to dryness. The residue was taken up in DCM (10 mL), slurried for 30 min. and filtered to give the title compound as a white solid. (400 mg, 17% yield).

[0158] The product had NMR data equivalent to those reported in the supporting information associated with Bolli et al., J. Med. chem. (2012), 55, 7849-7861.

[0159] LC-MS (method 1); tR = 1.57 min; 98.4% y/y. Variant VI:

[0160] A mixture of the compound of example 2 (100 g; 0.213 mol; 1.0 eq.), sulfamide (40.9 g; 0.425 mol; 2.0 eq.), K2CO3 (147 g) and DMSO (500 mL) was heated at 70°C for 3 h. after cooling to RT, the mixture was filtered and the filter cake washed with 1:1 EA/iPrOAc (300 mL). The solution was treated with charcoal and rinsed with 1:1 EA/iPrOAc (300 mL), followed by addition of 1 M aq. NaOAc solution. (500 mL). The phase here was washed with EtOAc/iPrOAc (1:1 (500 mL). Slow addition of 1 M H2SO4 (200 mL) led to crystallization of the crude product, which was washed twice with water (2 x 1 L). was slurried in water (1 L) at RT for 3 h. After filtration and washing with water (1 L), the material was dried to give the title compound as an off-white solid (75 g, 65% yield) .

[0161] The product had NMR data equivalent to those reported in the supporting information associated with Bolli et al., J. Med. chem. (2012), 55, 7849-7861.

[0162] LC-MS (method 3): tR = 3.77 min; 99.5% purity.

Variant VII:

[0163] A mixture of the compound of example 1 (10.00 g; 20.6 mmol; 1.0 eq.), cesium fluoride (9.378 g; 61.7 mmol; 3.0 eq.) and DMSO (25 mL) was stirred at 70°C for 2.5 h. Potassium carbonate (14.2 g; 103 mmol; 5.0 eq.) and sulfamide (3.95 g; 41.1 mmol; 2.0 eq.) were added and heating continued for a further 3 h. After cooling to RT, the mixture was filtered and the filter cake washed with EA/iPrOAc 1:1 (50 mL). The combined filtrate was acidified with 1 M H2SO4 (10 mL) to give a cloudy solution. Addition of water (50 ml) caused a suspension to form. The solid was filtered, washed twice with water (2x100ml) and dried to give the title compound as a white powder (8.6g, 77% yield.

[0164] The product had NMR data equivalent to those reported in the supporting information associated with Bolli et al., J. Med. chem. (2012), 55, 7849-7861.

Example 4: Preparation of propylsulfamic acid {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide (macitentan ): Variant I:

[0165] The compound of Example 1 (10 g; 20.6 mmol), propyl sulfamide (3.1 g; 22.6 mmol; 1.1 eq., prepared as described in Bolli et al., J. Med. Chem. (2012), 55, 7849-7861), TBAF.3H2O (19.5 g; 61.7 mmol; 3 eq.) and potassium carbonate (8.5 g; 61.7 mmol; 3 eq.) were suspended in DMSO (100ml). The mixture was heated at 100°C for 1 h and then cooled to 20-25°C. Water (100 mL) and DCM (100 mL) were added. The org layer. was washed 3 times with water (100 ml each time), aq. HCl (100 mL) and water (100 mL) before being concentrated under reduced pressure to dryness. The residue was suspended in EA (15 mL) and heated to reflux. Hept (30 mL) was added. The mixture was allowed to cool to 20-25°C on its own. The precipitate was filtered and rinsed with Hept (10 mL). The beige solid thus collected (11.0g) was recrystallized from EA (30ml) and Hept (25ml) to give the title compound as a white solid (6.4g; 53% yield).

[0166] The product had NMR and MS data equivalent to those reported in Bolli et al., J. Med. chem. (2012), 55, 7849-7861.

[0167] LC-MS (method 1): tR = 1.89 min; 100% y/y.

Variant II:

[0168] The compound of example 2 (2 g; 4.25 mmol), propyl sulfamide (735 mg; 5.32 mmol; 1.2 eq.; prepared as described in Bolli et al., J. Med. Chem. (2012), 55 , 7849-7861), cesium fluoride (2.0 g; 12.8 mmol; 3 eq.) and potassium carbonate (1.7 g; 12.8 mmol; 3 eq.) were suspended in DMSO (20 mL) at 20-25°C. The mixture was heated at 70-75 °C for 15 h. Water (20 mL) and DCM (20 mL) were added. The layers were separated and the org. was washed with aq. to 30% (20 mL) before being concentrated to dryness. The residue was recrystallized from toluene to give the title compound as a white powder (600 mg; 24% yield).

[0169] The product had MS and NMR data equivalent to those reported in Bolli et al., J. Med. chem. (2012), 55, 7849-7861.

[0170] LC-MS (method 1); tR = 1.83 min; 96.7% y/y.

Example 5: Preparation of Benzylsulfamic acid {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide:

[0171] The compound of Example 2 (14 g; 28.7 mmol), benzyl sulfamide potassium salt (7.09 g; 31.6 mmol; 1.1 eq.; prepared as described in Bolli et al., J.Med. Chem (2012), 55, 7849-7861), TBAF.3H2O (27.2 g; 86.2 mmol; 3 eq.) and potassium carbonate (15.9 g, 115 mmol; 4 eq.) were suspended in DMSO (140 mL) at 20-25°C. The mixture was heated at 100-105 °C for 1 h. At this point, LC-MS (Method 1) indicated complete conversion. The reaction mixture was cooled to 10-15°C. Water (140 mL) and DCM (140 mL) were added. The layers were separated and the org. was washed twice with water (140 mL), aq. 10% solution (140 mL) and with water (140 mL). It was concentrated under reduced pressure. The oily residue was purified by flash chromatography on silica gel (eluent: Hept/EA) to give the title compound as a white solid (4.75 g, 26% yield).

[0172] The product had NMR data equivalent to those reported in Bolli et al., J. Med. chem. (2012), 55, 7849-7861.

[0173] [M+1]+ = 635 and 637.

[0174] LC-MS (method 1): tR = 1.94 min; 81.0% y/y.

Claims (9)

1. Process for manufacturing the compound of formula I:

in which R is n-propyl, or a salt thereof, the process characterized by comprising the reaction of the compound of formula I-1:

where X is bromine, chlorine or fluorine, with the compound of formula I-2:

wherein R is n-propyl, or a salt of the compound of formula I-2, said reaction being carried out in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents, and when X is bromine or chlorine, in the presence of tetra-n-butyl ammonium fluoride hydrate or cesium fluoride. 2. Process according to claim 1, characterized in that the base is selected from the group consisting of NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, tert-butylate of potassium, Na2CO3, K2CO3 and CS2CO3. 3. Process, according to claim 2, characterized by the fact that the base is K2CO3. 4. Process according to any one of claims 1 to 3, characterized in that the polar aprotic organic solvent or polar mixture of aprotic organic solvents comprises dimethyl sulfoxide. 5. Process according to claim 4, characterized in that it is carried out using dimethyl sulfoxide as solvent. 6. Process according to any one of claims 1 to 5, characterized in that X is chlorine and the reaction of the compound of formula I-1 with the compound of formula I-2 is carried out in the presence of fluoride hydrate of tetra-n-butyl ammonium and using dimethyl sulfoxide as solvent. 7. Process according to claim 1, characterized in that it comprises the following steps: a) the reaction of the compound of formula I-1cl:

or a salt thereof, with tetra n-butyl ammonium fluoride hydrate or cesium fluoride in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents, to provide the compound of formula I-1F:

b) the reaction of the compound of formula I-1F obtained in step a) with a compound of formula I-2:

wherein R is n-propyl, or a salt thereof, in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents to provide the compound of formula I or a salt thereof; wherein each of the aprotic organic solvents or polar mixtures of aprotic organic solvents used in step a) and step b) are independently selected from dimethyl sulfoxide, a mixture of two solvents, wherein the first of these two solvents is selected from the group consisting in toluene and dichloromethane and the second of these two solvents is dimethylsulfoxide and a mixture of toluene, dichloromethane and dimethylsulfoxide. 8. Process according to claim 7, characterized in that step a) is performed by reacting the compound of formula I-1Cl with cesium fluoride. 9. Use of a compound of formula I-1:

wherein X is bromine, chlorine or fluorine, or a salt thereof, characterized in that it is in a process for the manufacture of the compound of formula I, as defined in claim 1, or a salt thereof.